As with many NYCRR stations in New York City, the station became a Penn Central station once the NYC & Pennsylvania Railroads merged in 1968. The New Haven Line and its branches would be acquired by Penn Central a year later, thus making it a full Penn Central station. Penn Central's continuous financial despair throughout the 1970s forced them to turn over their commuter service to the Metropolitan Transportation Authority. After the 138th Street in the Mott Haven section of the South Bronx was closed by Penn Central in 1972, 125th Street Station was the northernmost station to be shared by the Hudson and Harlem Lines. The station and the railroad were turned over to Conrail in 1976, and eventually became part of the MTA's Metro-North Railroad in 1983.

A six-year-long renovation of the 1897 structure was completed in 1999 and cleared out a century's worth of neglect and deterioration.[1] The entire Park Avenue viaduct was replaced piece-by-piece without disturbing Metro-North service for the duration of the renovation. This reconstruction included the removal of the Nick Tower just south of the station. The Nick Tower was a control tower mounted over the tracks spanning the entire right-of-way.[2] The renovation is considered a replication, rather than renovation, of the original 1930s version of the station being that none of the original structure is visible to the public.

The station is used for travel to and from suburbs north of New York City and the Bronx rather than travel to and from Grand Central Terminal. Except for off-peak local trains on the Harlem and Hudson Lines, northbound trains stop at the station only to receive passengers while southbound trains stop only to discharge passengers. It is in the same fare zone as Grand Central Terminal, so customers pay the same fare whether traveling to Harlem or Grand Central, and may use either station.

There are two high-level island platforms, each serving two tracks. During rush hours, three tracks are typically assigned to the peak direction, with the remaining track serving the reverse direction.

The station's former New York Central Railroad comfort station across 125th Street, which has been abandoned for a long time.

The south side of 125th Street below the station viaduct houses a long-abandoned former comfort station (restroom facility) and the block has long been a vacant lot attracting garbage.[3] The New York City Economic Development Corporation announced in 2013 that they would work with a mix of public agencies and private developers to improve the area surrounding the station, long considered a blight on East 125th Street.[4]

Ridership at Harlem–125th Street station rose 55% between 2002 and 2013, much of which included reverse commuters—city residents accessing jobs in the suburbs.

Phase II of the Second Avenue Subway is currently slated to end below the Metro-North station, with the subway tracks heading east below 125th Street.[5] The line would be built deep below the ground, below the Lexington Avenue Line.